1. Technical Field
The present invention relates generally to systems for trace gas detection, and more particularly, to high-throughput screening of combinatorial libraries using an optical spectroscopy system.
2. Discussion
Combinatorial chemistry refers generally to a group of methods for creating chemical libraries--vast collections of compounds of varying structure--that are tested or screened in order to identify a subset of promising compounds. Libraries may consist of molecules free in solution, bound to solid particles, or arrayed on a solid surface.
Combinatorial chemistry has changed the way many scientists develop new and useful compounds. For example, workers in the pharmaceutical industry have successfully used such techniques to dramatically increase the speed of drug discovery. Material scientists have employed combinatorial methods to develop novel high temperature superconductors, magnetoresistors, and phosphors. More recently, scientists have applied combinatorial methods to aid in the development of catalysts. See, for example, copending U.S. patent application Ser. No. 08/327,513 "The Combinatorial Synthesis of Novel Materials" (published as WO 96/11878) and copending U.S. patent application Ser No. 08/898,715 "Combinatorial Synthesis and Analysis of Organometallic Compounds and Catalysts" (published as WO 98/03521), which are both herein incorporated by reference.
As with any new technology, combinatorial chemistry is not without problems. Once a researcher creates combinatorial libraries, he or she faces the daunting task of screening tens, hundreds or even thousands of compounds for one or more properties of interest. Although automating existing assays does provide a partial solution, traditional analytical methods are often ill-suited to screening large combinatorial libraries.
This is especially true in catalyst development, where, for a given reaction, the best catalysts are typically those that produce the most product in the shortest amount of time. Unlike traditional catalyst development, combinatorial methods do not permit the synthesis and testing of large amounts of a particular catalyst. Instead, minute quantities of each catalyst are typically deposited on a solid substrate--in the wells of a microtiter plate, for example--and the entire substrate is placed in a reaction vessel where individual catalysts are exposed to reactants. Catalyst library members thus comprise no more than about a few to a few hundred .mu.g of material, resulting in extremely small production rates (.apprxeq.1 .mu.g/s) and correspondingly low reaction product concentrations (&lt;1 ppm).
Although the small production rates and low product concentrations associated with catalyst screening rule out many traditional analytical techniques, one viable approach is direct mass spectrometric detection, which is described in commonly assigned copending U.S. patent application Ser. No. 08/946,730, "Mass Spectrometers and Methods for Rapid Screening of Libraries of Different Materials," filed Oct. 8, 1997 (Attorney Docket No. 016703-000910), which is herein incorporated by reference. Other analytical techniques, such as photothermal detection spectroscopy and four-wave mixing spectroscopy, also appear promising because of their rapid response time and their ability to detect chemical species at extremely low concentrations (1-10 ppb). However, as discussed below, these optical spectroscopic methods, as currently practiced, are often unsuitable for screening combinatorial libraries.
Photothermal detection spectroscopy, which includes photothermal deflection, photoacoustic spectroscopy, thermal lensing, and interferometry, have been successfully used for trace gas detection. In all four methods, light from a cylindrical pump laser is passed through a sample containing a carrier gas and a chemical species of interest (analyte). Though the carrier gas is not directly affected by the laser light, the individual analyte molecules absorb the light energy and are "excited." The excited analyte molecules collide with neighboring carrier gas molecules, resulting in local heating in the vicinity of the laser light. The magnitude of the local heating is proportional to the number of excited analyte molecules, and can be used to determine the analyte concentration.
The four photothermal detection methods differ in the way the local heating is measured. For example, photothermal deflection spectroscopy (PTD) relies on a change in refractive index due to local heating of the sample gas. A second (probe) laser beam is directed into the locally heated region, and is deflected from its original path because of the change in refractive index. The degree of deflection can be measured, and is directly proportional to the concentration of the analyte. A general discussion of photothermal detection methods, and of PTD in particular, can be found in R. L. Zimering et al., 36 (15) Applied Optics 3188 (1997), and H. S. M. DeVries et al., 36(1) Infrared Physics and Technology 483 (1995), which are herein incorporated by reference.
Four-wave mixing spectroscopy is similar to PTD, thermal lensing, and interferometry in that it relies on local changes in the index of refraction of a sample gas. In a typical four-wave mixing setup, two laser beams are directed to intersect each other. In the overlap region, a periodic light intensity pattern (bright and dark) is created due to constructive and destructive interference of the two laser beams. At the crests of the light intensity pattern, more analyte molecules are excited than at the valleys of the intensity pattern. As in the case of the other thermal detection methods, the excited molecules collide with neighboring carrier gas molecules and the radiative energy absorbed is converted to thermal energy. The crest regions of the medium experience a higher temperature rise than the valley regions. Thus, the periodic light intensity pattern results in a spatially periodic temperature pattern, which for a gas medium, gives rise to a spatially equivalent, periodic density pattern. Since refractive index in the gas phase decreases with decreasing density, a refractive index grating is formed where the two laser beams overlap. This type of grating is commonly referred to as a thermal grating. When a third laser beam is directed at this refractive index grating, a portion of it is diffracted. The magnitude of the diffracted beam, which is detected as the signal, is a measure of the concentration of the analyte. There are a total of four laser fields involved, including the signal field, hence the name "four-wave mixing." This method is described in Wu & Tong, 65 Analytical Chem. 112 (1993), which is herein incorporated by reference.
Four-wave mixing and the photothermal detection methods are in many instances unsuitable for screening large libraries of catalytic materials because their sensitivity is limited by the sample pressure. For example, in PTD the signal strength, S, is related to the analyte concentration, C, and the sample total pressure, P, through the relationship: EQU S=.alpha..multidot.C.multidot.P I
where .alpha. is a proportionality constant. Given that there is some acceptable minimum value of S in which the signal strength is greater than some multiple of the background noise, decreasing the sample total pressure will result in an increase in the lower detection limit (LDL) of the analyte.
The loss in sensitivity with P is especially troublesome when screening combinatorial catalyst libraries through remote detection of C. As discussed above, the concentration of the analyte and its production rate at the catalyst surface are extremely low in combinatorial library screening. Therefore, researchers often use a capillary tube to transport the analyte from the catalyst surface within the reactor to a remote detection cell where they make the PTD measurement. The time it takes to fill the cell with the sample gas increases with decreasing pressure difference between the reactor and the detection cell. Assuming a 1 m long capillary tube with a 0.1 mm ID, a 1 cm.sup.3 detection cell, and a reactor pressure of 760 torr, the time to achieve a particular sample pressure within the detection cell and its affect on the lower detection limit of the analyte can be seen in Table 1.
TABLE 1 ______________________________________ Dependence of Fill Time & Lower Detection Limit, LDL, on Sample Total Pressure, P Time to Fill Cell P, torr with Sample, s LDL, ppb ______________________________________ 1 &lt;1 5.8 .times. 10.sup.5 10 .apprxeq.10 5.8 .times. 10.sup.3 100 .apprxeq.100 58 760 .infin. 1 ______________________________________
Thus, relatively long fill times are needed to detect chemical species below about 50 ppb, which would compromise the speed at which the catalyst library members are screened.
In situ detection might solve the problem of sensitivity loss with decreasing P, but its use with combinatorial library screening is problematic. Although catalytic products can be detected by directing the pump and probe laser beams within the reactor, the arrangement would result in an unacceptable loss of accuracy. Because of the low production rate of analyte, even if the detection volume (i.e., the region of local heating) is located about 1 mm above the catalyst surface, the measured concentration will be about a thousand-fold less than the concentration at the catalyst surface. Although library screening does not necessarily require knowledge of the analyte concentration at the surface of the catalyst, surface concentrations of 100 ppb or less would be undetectable since the lower detection limit of PTD is about 1 ppb. Moreover, in situ PTD measurements of combinatorial libraries are susceptible to cross contamination because adjacent catalysts are often no more than 2 mm apart. In such cases, cross contamination is likely if large disparities in catalytic activity exist between adjacent compounds.
The present invention is directed to overcoming, or at least minimizing, one or more of the problems set forth above.